ORCID Profile
0000-0002-0343-3990
Current Organisation
University of California, San Diego
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Publisher: MDPI AG
Date: 29-07-2022
Abstract: Macrophages undergo a metabolic switch from oxidative phosphorylation to glycolysis when exposed to gram-negative bacterial lipopolysaccharide (LPS), which modulates antibacterial host defence mechanisms. Here, we show that LPS treatment of macrophages increased the classical oxidative burst response via the NADPH oxidase (NOX) 2 enzyme, which was blocked by 2-deoxyglucose (2-DG) inhibition of glycolysis. The inhibition of the pentose phosphate pathway with 6-aminonicotinamide (6-AN) also suppressed the LPS-induced increase in NOX2 activity and was associated with a significant reduction in the mRNA expression of NOX2 and its organizer protein p47phox. Notably, the LPS-dependent enhancement in NOX2 oxidase activity was independent of both succinate and mitochondrial reactive oxygen species (ROS) production. LPS also increased type I IFN-β expression, which was suppressed by 2-DG and 6-AN and, therefore, is dependent on glycolysis and the pentose phosphate pathway. The type I IFN-β response to LPS was also inhibited by apocynin pre-treatment, suggesting that NOX2-derived ROS promotes the TLR4-induced response to LPS. Moreover, recombinant IFN-β increased NOX2 oxidase-dependent ROS production, as well as NOX2 and p47phox expression. Our findings identify a previously undescribed molecular mechanism where both glycolysis and the pentose phosphate pathway are required to promote LPS-induced inflammation in macrophages.
Publisher: Frontiers Media SA
Date: 04-05-2022
DOI: 10.3389/FCIMB.2022.883448
Abstract: Endosomal NOX2 oxidase-dependent ROS production promotes influenza pathogenicity, but the role of NOX4 oxidase, which is highly expressed in the lung endothelium, is largely unknown. The aim of this study was to determine if endothelial NOX4 expression can influence viral pathology in vivo , using a mouse model of influenza infection. WT and transgenic endothelial NOX4 overexpressing mice ( NOX4 TG) were infected intranasally with the Hong Kong H3N2 X-31 influenza A virus (10 4 PFU HK x-31) or PBS control. Mice were culled at either 3 or 7 days post-infection to analyse: airway inflammation by bronchoalveolar lavage fluid (BALF) cell counts NOX4 , as well as inflammatory cytokine and chemokine gene expression by QPCR and ROS production by an L-012-enhanced chemiluminescence assay. Influenza A virus infection of WT mice resulted in a significant reduction in lung NOX4 mRNA at day 3, which persisted until day 7, when compared to uninfected mice. Influenza A virus infection of NOX4 TG mice resulted in significantly less weight loss than that of WT mice at 3-days post infection. Viral titres were decreased in infected NOX4 TG mice compared to the infected WT mice, at both 3- and 7-days post infection and there was significantly less lung alveolitis, peri-bronchial inflammation and neutrophil infiltration. The oxidative burst from BALF inflammatory cells extracted from infected NOX4 TG mice was significantly less than that in the WT mice. Expression of macrophage and neutrophil chemoattractants CXCL10, CCL3, CXCL1 and CXCL2 in the lung tissue were significantly lower in NOX4 TG mice compared to the WT mice at 3-days post infection. We conclude that endothelial NOX4 oxidase is protective against influenza morbidity and is a potential target for limiting influenza A virus-induced lung inflammation.
Publisher: Frontiers Media SA
Date: 23-03-2022
DOI: 10.3389/FPHAR.2022.870156
Abstract: There is an urgent need to develop effective therapeutic strategies including immunomodulators to combat influenza A virus (IAV) infection. Influenza A viruses increase ROS production, which suppress anti-viral responses and contribute to pathological inflammation and morbidity. Two major cellular sites of ROS production are endosomes via the NOX2-oxidase enzyme and the electron transport chain in mitochondria. Here we examined the effect of administration of Cgp91ds-TAT, an endosome-targeted NOX2 oxidase inhibitor, in combination with mitoTEMPO, a mitochondrial ROS scavenger and compared it to monotherapy treatment during an established IAV infection. Mice were infected with IAV (Hkx31 strain 10 4 PFU/mouse) and 24 h post infection were treated with Cgp91ds-TAT (0.2 mg/kg), mitoTEMPO (100 μg) or with a combination of these inhibitors [Cgp91ds-TAT (0.2 mg/kg)/mitoTEMPO (100 μg)] intranasally every day for up to 2 days post infection (pi). Mice were euthanized on Days 3 or 6 post infection for analyses of disease severity. A combination of Cgp91ds-TAT and mitoTEMPO treatment was more effective than the ROS inhibitors alone at reducing airway and neutrophilic inflammation, bodyweight loss, lung oedema and improved the lung pathology with a reduction in alveolitis following IAV infection. Dual ROS inhibition also caused a significant elevation in Type I IFN expression at the early phase of infection (day 3 pi), however, this response was suppressed at the later phase of infection (day 6 pi). Furthermore, combined treatment with Cgp91ds-TAT and mitoTEMPO resulted in an increase in IAV-specific CD8 + T cells in the lungs. In conclusion, this study demonstrates that the reduction of ROS production in two major subcellular sites, i.e. endosomes and mitochondria, by intranasal delivery of a combination of Cgp91ds-TAT and mitoTEMPO, suppresses the severity of influenza infection and highlights a novel immunomodulatory approach for IAV disease management.
Publisher: Proceedings of the National Academy of Sciences
Date: 21-09-2020
Abstract: Influenza infection during pregnancy is associated with increased maternal and perinatal complications. Here, we show that, during pregnancy, influenza infection leads to viral dissemination into the aorta, resulting in a peripheral “vascular storm” characterized by enhanced inflammatory mediators the influx of Ly6C monocytes, neutrophils, and T cells and impaired vascular function. The ensuing vascular storm induced hypoxia in the placenta and fetal brain and caused an increase in circulating cell free fetal DNA and soluble Flt1 release. We demonstrate that vascular dysfunction occurs in response to viral infection during pregnancy, which may explain the high rates of morbidity and mortality in pregnant dams, as well as the downstream perinatal complications associated with influenza infection.
Publisher: Springer Science and Business Media LLC
Date: 20-02-2019
DOI: 10.1038/S41598-019-38864-5
Abstract: Toll-like receptor 7 (TLR7) is a pattern recognition receptor that recognizes viral RNA following endocytosis of the virus and initiates a powerful immune response characterized by Type I IFN production and pro-inflammatory cytokine production. Despite this immune response, the virus causes very significant pathology, which may be inflammation-dependent. In the present study, we examined the effect of intranasal delivery of the TLR7 agonist, imiquimod or its topical formulation Aldara, on the inflammation and pathogenesis caused by IAV infection. In mice, daily intranasal delivery of imiquimod prevented peak viral replication, bodyweight loss, airway and pulmonary inflammation, and lung neutrophils. Imiquimod treatment also resulted in a significant reduction in pro-inflammatory neutrophil chemotactic cytokines and prevented the increase in viral-induced lung dysfunction. Various antibody isotypes (IgG1, IgG2a, total IgG, IgE and IgM), which were increased in the BALF following influenza A virus infection, were further increased with imiquimod. While epicutaneous application of Aldara had a significant effect on body weight, it did not reduce neutrophil and eosinophil airway infiltration indicating less effective drug delivery for this formulation. We concluded that intranasal imiquimod facilitates a more effective immune response, which can limit the pathology associated with influenza A virus infection.
Publisher: Frontiers Media SA
Date: 17-05-2022
DOI: 10.3389/FNMOL.2022.893083
Abstract: Neurocognitive dysfunction is present in up to ∼61% of people with chronic obstructive pulmonary disease (COPD), with symptoms including learning and memory deficiencies, negatively impacting the quality of life of these in iduals. As the mechanisms responsible for neurocognitive deficits in COPD remain unknown, we explored whether chronic cigarette smoke (CS) exposure causes neurocognitive dysfunction in mice and whether this is associated with neuroinflammation and an altered neuropathology. Male BALB/c mice were exposed to room air (sham) or CS (9 cigarettes/day, 5 days/week) for 24 weeks. After 23 weeks, mice underwent neurocognitive tests to assess working and spatial memory retention. At 24 weeks, mice were culled and lungs were collected and assessed for hallmark features of COPD. Serum was assessed for systemic inflammation and the hippoc us was collected for neuroinflammatory and structural analysis. Chronic CS exposure impaired lung function as well as driving pulmonary inflammation, emphysema, and systemic inflammation. CS exposure impaired working memory retention, which was associated with a suppression in hippoc al microglial number, however, these microglia displayed a more activated morphology. CS-exposed mice showed changes in astrocyte density as well as a reduction in synaptophysin and dendritic spines in the hippoc us. We have developed an experimental model of COPD in mice that recapitulates the hallmark features of the human disease. The altered microglial/astrocytic profiles and alterations in the neuropathology within the hippoc us may explain the neurocognitive dysfunction observed during COPD.
Publisher: Wiley
Date: 15-12-190728635
DOI: 10.1002/HFM.20749
Publisher: Mary Ann Liebert Inc
Date: 05-2019
Publisher: Mary Ann Liebert Inc
Date: 05-2020
Location: United States of America
No related grants have been discovered for Jonathan Erlich.